Naja atra venom peptide reduces pain by selectively blocking the voltage-gated sodium channel Nav1.8
Naja atra venom peptide reduces pain by selectively blocking the voltage-gated sodium channel Nav1.8
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眼镜蛇毒肽通过选择性阻断电压门控钠通道 Nav1.8 来减轻疼痛
DOI：
10.1074/jbc.ra118.007370
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发表时间：
2019-02
影响因子：
4.8
通讯作者：
Liu Zhonghua
中科院分区：
文献类型：
--
作者：
Zhang Fan;Zhang Changxin;Xu Xunxun;Zhang Yunxiao;Gong Xue;Yang Zuqin;Zhang Heng;Tang Dongfang;Liang Songping;Liu Zhonghua
电压门控钠通道Nav1.8优先在外周伤害感受神经元中表达，并促进炎症性和神经性疼痛。因此，Nav1.8已成为缓解疼痛的最有前途的镇痛靶点之一。通过大规模筛选各种动物源性毒素和毒液中的Nav1.8抑制剂，我们在这里鉴定了μ-EPTX-Na 1a，一种来自中国眼镜蛇（Naja atra）毒液的62个残基的三指肽，作为Nav1.8的有效抑制剂，表现出对其他电压门控钠通道亚型的高选择性。使用全细胞电压钳记录，我们观察到纯化的μ-EPTX-Na 1a阻断Nav1.8电流。这种阻断与激活的去极化转变和失活的复极化转变有关，这是一种不同于迄今为止鉴定的任何其他门控修饰毒素的机制。在炎症和神经病理性疼痛的啮齿动物模型中，μ-EPTX-Na 1a比吗啡更有效地减轻伤害性行为，表明μ-EPTX-Na 1a具有强效镇痛作用。μ-EPTX-Na 1a在小鼠中未显示出明显的细胞毒性和心脏毒性，即使在比产生显著镇痛作用的剂量高30倍的剂量下也未产生明显的不良反应。我们的研究确定μ-EPTX-Na 1a是开发Nav1.8靶向镇痛药以管理疼痛的有希望的领导者。
The voltage-gated sodium channel Nav1.8 is preferentially expressed in peripheral nociceptive neurons and contributes to inflammatory and neuropathic pain. Therefore, Nav1.8 has emerged as one of the most promising analgesic targets for pain relief. Using large-scale screening of various animal-derived toxins and venoms for Nav1.8 inhibitors, here we identified μ-EPTX-Na1a, a 62-residue three-finger peptide from the venom of the Chinese cobra (Naja atra), as a potent inhibitor of Nav1.8, exhibiting high selectivity over other voltage-gated sodium channel subtypes. Using whole-cell voltage-clamp recordings, we observed that purified μ-EPTX-Na1a blocked the Nav1.8 current. This blockade was associated with a depolarizing shift of activation and repolarizing shift of inactivation, a mechanism distinct from that of any other gating modifier toxin identified to date. In rodent models of inflammatory and neuropathic pain, μ-EPTX-Na1a alleviated nociceptive behaviors more potently than did morphine, indicating that μ-EPTX-Na1a has a potent analgesic effect. μ-EPTX-Na1a displayed no evident cytotoxicity and cardiotoxicity and produced no obvious adverse responses in mice even at a dose 30-fold higher than that producing a significant analgesic effect. Our study establishes μ-EPTX-Na1a as a promising lead for the development of Nav1.8-targeting analgesics to manage pain.
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影响因子：
5
作者：
Zhonglin Han;Yu Jiang;Feng Xiao;K. Cao;Dao-wu Wang
通讯作者：
Zhonglin Han;Yu Jiang;Feng Xiao;K. Cao;Dao-wu Wang
狼蛛毒素揭示了结构域 II 和 IV 的协同作用是 Na(v)1.3 中持续电流产生的基础
影响因子：
4.6
作者：
Tang C;Zhou X;Zhang Y;Xiao Z;Hu Z;Zhang C;Huang Y;Chen B;Liu Z;Liang S
通讯作者：
Liang S
DOI：
10.1155/2012/364741
发表时间：
2012
期刊：
Evidence-based complementary and alternative medicine : eCAM
影响因子：
--
作者：
Huang CC;Hsu MC;Huang WC;Yang HR;Hou CC
通讯作者：
Hou CC
DOI：
10.1523/jneurosci.23-01-00158.2003
发表时间：
2003-01
期刊：
The Journal of Neuroscience
影响因子：
--
作者：
M. Gold;D. Weinreich;Chang-Sook Kim;Ruizhong Wang;J. Treanor;F. Porreca;J. Lai
通讯作者：
M. Gold;D. Weinreich;Chang-Sook Kim;Ruizhong Wang;J. Treanor;F. Porreca;J. Lai
影响因子：
4.8
作者：
Po-long Wu;Shao‐Chen Lee;Chia-Chen Chuang;S. Mori;N. Akakura;Wen‐guey Wu;Y. Takada
通讯作者：
Po-long Wu;Shao‐Chen Lee;Chia-Chen Chuang;S. Mori;N. Akakura;Wen‐guey Wu;Y. Takada